Boceprevir-Based Triple Antiviral Therapy for Chronic Hepatitis C Virus Infection in Kidney-Transplant Candidates

Background. There are few data on the combination of (pegylated-) interferon- (Peg-IFN-) α, ribavirin, and first-generation direct-acting antiviral agents (DAAs). Our aim was to describe the efficacy and safety of Peg-IFN-α, ribavirin, and boceprevir in hemodialysis patients. Patients. Six hemodialysis patients, chronically infected by genotype-1 HCV, were given Peg-IFN-α (135 µg/week), ribavirin (200 mg/d), and boceprevir (2400 mg/d) for 48 weeks. Results. At initiation of antiviral therapy, median viral concentration was 5.68 (3.78–6.55) log IU/mL. HCV RNA was undetectable in four of the six patients at week 4 and in all patients at week 24. A breakthrough was observed in two patients between weeks 24 and 48, and a third patient stopped antiviral therapy between weeks 24 and 48 because of severe peripheral neuropathy. At week 48, HCV RNA was undetectable in three patients. Of these, two patients relapsed within a month after antiviral therapy was stopped. Hence, only one patient had a sustained virological response; he was a previous partial responder. Overall, anemia was the main side effect. Conclusion. A triple antiviral therapy based on Peg-IFN-α, ribavirin, and boceprevir is not optimal at treating hemodialysis patients with chronic HCV infection. Studies using new-generation drugs are required in this setting.


Introduction
Chronic hepatitis C virus (HCV) infection has a detrimental effect on the health of persons with chronic kidney disease [1]. It leads to higher mortality in maintenance hemodialysis patients compared to noninfected patients and reduces the survival rates of patients undergoing kidney transplantation as well as their grafts [2]. It renders patients with a higher risk of developing diabetes mellitus, de novo or recurrent membranoproliferative glomerulonephritis, lymphoproliferative disorders, and fibrosing cholestatic hepatitis after kidney transplantation [3].
Until recently, in the absence of any efficient treatment for HCV infection after kidney transplantation, treating all anti-HCV-positive RNA-positive patients that were candidates for kidney transplantation has been recommended [4].
For several years, standard reduced interferon-(IFN-) alpha or pegylated-(Peg-) IFN--2a, given as a monotherapy, has been the main treatment given to hemodialysis patients with HCV replication [4]. Because ribavirin has been found to be responsible for hemolytic anemia in patients with impaired kidney function [5] as well as in hemodialysis patients, it was first prohibited and then used at markedly reduced daily doses with careful monitoring for anemia 2 Journal of Transplantation and other adverse effects [1]. HCV-positive dialysis patients that received standard IFN-or Peg-IFN-achieved ≈50% efficacy [6].
First-generation direct-acting antiviral agents (DAAs), such as the protease inhibitors telaprevir and boceprevir, have been developed over the past few years. They have been introduced as an adjunctive therapy for patients with chronic HCV but normal kidney function and have significantly improved the SVR [7]. However, scarce data regarding their use in hemodialysis patients have been published [8][9][10]. In addition, no data regarding the use of new-generation DAAs, such as sofosbuvir, daclatasvir, simeprevir, or ledipasvir, have been reported in this setting.
The aim of this study was to assess the efficacy and safety of a combined therapy of Peg-IFN, ribavirin, and boceprevir to treat anti-HCV-positive RNA-positive hemodialysis patients who were candidates for kidney transplantation.

Patients and Methods
Between February 2013 and September 2014, six patients who were chronically infected by genotype-1 HCV and were receiving hemodialysis three times weekly, and who were candidates for kidney transplantation, were treated with Peg-IFN, ribavirin, and boceprevir as a triple therapy, after having given their written informed consent. The study was approved by Toulouse University's IRB. The patients' characteristics are presented in Table 1. There were three men and three women, ranging in age from 39 to 72 years (median: 49.5). Four were candidates for a second or third transplantation. Five of the six patients had previously received interferon for HCV infection: one had a relapse and the other four patients were partial responders.
Peg-IFN was given at the dose of 135 g/week. Ribavirin was given at the dose of 200 mg/d, three times a week, after each dialysis session. Boceprevir was given at the dose of 800 mg t.i.d. There was no lead-in therapy phase. Therapy was scheduled to last 48 weeks.
A rapid virological response was defined as undetectable HCV RNA at week 4. A sustained virological response was defined as negative HCV RNA six months after the end of therapy. A virological breakthrough was defined as HCV replication during therapy and after a period of nonviral replication.
Patients were followed up every 15 days during the first month and then at three-month intervals for 6 months after therapy was completed. HCV RNA was assessed using the quantitative COBAS Amplicor HCV monitor assay (limit of detection 15 log IU/mL).

Virological Response.
At the initiation of antiviral therapy, median viral concentration was 5.68 (4.3-6.55) log IU/mL. The evolution of HCV concentration is presented in Figure 1. A rapid virological response, that is, undetectable HCV RNA at week 4, was observed in four of the six patients (66.6%). All patients had at least once undetectable HCV RNA during therapy, and HCV RNA was undetectable in all patients at week 24. However, a breakthrough was observed in two patients (P3 and P4) between weeks 24 and 48, and a third patient (P2) had to stop antiviral therapy between weeks 24 and 48 because of severe peripheral neuropathy. At week 48, overall, when therapy was scheduled to finish, HCV RNA was undetectable in three patients. However, of these, two patients relapsed within the month after antiviral therapy had finished. Hence, overall, only one patient (16.7%) had a sustained virological response: he had been a previous partial responder.

Biochemical Response.
As is usually observed in hemodialysis patients, liver-enzyme levels were within the normal ranges at the beginning of therapy and also at the end of therapy (data not shown).

Modifications and Tolerance to Antiviral Therapy.
Because of fatigue and a flu-like syndrome, Peg-IFN doses were decreased at week 4 from 135 to 90 g/week in three patients (P2, P3, and P4) and then decreased further at week 24 from 90 to 45 g/week in one patient (P4). One patient (P2) developed peripheral neuropathy that was attributed to the antiviral therapy, which was stopped at week 28 although the patient was nonviremic.
Ribavirin dose was reduced at week 24 to 200 mg/week in one patient (P4) because of very severe anemia, despite receiving high doses of recombinant erythropoietin.

Discussion
Within the last few years, the first-generation DAA NS3-4A protease inhibitors, that is, boceprevir and telaprevir, have been developed and used in combination with peg-interferon and ribavirin to treat patients with chronic HCV infection [11]. Boceprevir-or telaprevir-based anti-HCV therapy was first used in immunocompetent patients that had preserved kidney function. It significantly improved the sustained virological rate in genotype-1 HCV infected patients, mainly for noncirrhotic patients [7]. In hemodialysis patients, the recommended treatment for chronic HCV infection remains standard or pegylatedinterferon [4]. As pointed out in a meta-analysis by Fabrizi et al., the SVR response was 39% after standard IFN-therapy and 31% when Peg-IFN-was used [6]. The dropout rates were, respectively, 19% and 27% [6]. In other studies, although ribavirin accumulates in hemodialysis patients and causes severe hemolytic anemia [5], low doses of ribavirin, that is, 200 mg/day or 200 mg every other day, when added to interferon, improved the SVR [1]. The SVR ranged from 17 to 70%, and the dropout rate was up to 50% [1].
Boceprevir-or telaprevir-based anti-HCV therapy has been used in a small number of hemodialysis patients. Dumortier et al. treated four hemodialysis patients with a combined therapy of Peg-IFN-, ribavirin, and telaprevir [8]. Three of their four patients achieved viral clearance at week 12; however, no further outcomes were reported, and the number of SVRs is unknown. Wiegand et al. treated seven hemodialysis patients with Peg-IFN-, ribavirin, and telaprevir [9]: the duration of treatment ranged from 24 to 47 weeks. A SVR was observed in six of their seven patients [9]. Finally, Knapstein et al. successfully treated a hemodialysis patient with Peg-IFN-, ribavirin, and boceprevir for 48 weeks [10].
In the present study, six patients were given Peg-IFN-, ribavirin, and boceprevir for 48 weeks. Antiviral therapy was stopped in one patient because of severe neuropathy, which was attributed to the interferon therapy. Two breakthrough events were observed in two patients, which required doses of antiviral drugs to be reduced because of adverse events. Overall, three patients were cleared of the virus by the end of therapy. However, two of these patients then relapsed one month and six months after treatment was finished. Hence, overall, only one patient had a sustained virological response.
Eight of the 14 hemodialysis patients that received antiviral triple therapy, who had a sufficiently long follow-up, and were included in either a previously published series or in the present study, had a sustained virological response (57%). The poor results observed in our study are probably related to poor tolerance to the antiviral therapy, which required dose reductions. Similar to previous studies, the main side effect observed in our study was anemia, which required the introduction of rEPO, or an increased dose of rEPO plus blood transfusions. Hence, this triple-therapy strategy did not effectively treat our hemodialysis patients with chronic HCV infection.
Very recently, the use of new-generation DAAs, that is, sofosbuvir combined with daclatasvir, simeprevir, or ledipasvir, has been shown to be highly efficient at treating HCV infection in cirrhotic and noncirrhotic immunocompetent patients [12][13][14][15][16], in liver-transplant patients [17][18][19] and in some kidney-transplant patients [20]. Individually, daclatasvir, simeprevir, and ledipasvir can be eliminated by the liver and so can be given to hemodialysis patients. However, no data regarding the use of sofosbuvir in patients with a glomerular-filtration rate <30 mL/min exist: hence, a combination of daclatasvir, simeprevir, or ledipasvir is still not recommended in this setting. A phase-II multicenter study has assessed the efficacy and safety of the combination of grazoprevir (MK-5172) and elbasvir (MK-8742) given to patients with chronic hepatitis and chronic kidney disease, including hemodialysis patients (ClinicalTrials.gov: NCT02092350).
In summary, a triple antiviral therapy based on Peg-IFN-, ribavirin, and either telaprevir or boceprevir did not optimally treat hemodialysis patients with chronic HCV infection. Studies using new-generation drugs are required in this population as well as for kidney-transplant patients.